6. Pharmacokinetics 4 Flashcards
How may a drug be excreted via the GIT?
Gastrointestinal Excretion
- Some drugs and their metabolites are excreted by the gastrointestinal tract in the faeces
- Drugs and metabolites may enter the gastrointestinal tract for excretion in a number of ways including
- transport by carrier proteins e.g. organic anion transports (OAT), organic cation transporters (OCT) and p-glycoprotein
- excretion in the bile (note enterohepatic circulation)
What is Enterohepatic Circulation?
Enterohepatic Circulation
- Exits the liver → Into gut → Reabsorbed back into liver (via portal system)
- Enterohepatic circulation occurs by biliary excretion and intestinal reabsorption of a compound, sometimes with hepatic conjugation and intestinal de-conjugation
- Many natural products including cholesterol, bile acids and oestrogen undergo enterohepatic circulation
Which drugs are excreted in the bile and may undergo enterohepatic circulation?
Enterohepatic Circulation - Examples
A number of drugs which are metabolised by Phase 2 conjugation with glucuronide are excreted in the bile and may undergo enterohepatic circulation
- e.g. morphine, paracetamol
What may intestinal reabsorption to complete the enterohepatic cycle depend on?
Intestinal reabsorption to complete the enterohepatic cycle may depend on hydrolysis of a drug conjugate by gut bacteria
What is the pharmacological significance of enterohepatic circulation and drug effects?
Enterohepatic circulation may prolong the pharmacological effect of some drugs
Which 2 types of reactions are involved in Drug Metabolism?
Drug Metabolism
Drug metabolism basically involves two types of reaction:
-
Phase 1 reactions → oxidation, reduction and hydrolysis
- e.g. by enzymes of the cytochrome P450 system
-
Phase 2 reactions → conjugation reactions and involve the attachment of a chemical group to the parent drug or metabolite
- e.g. glucuronidation, sulphation
How is estrogen metabolised?
Enterohepatic Circulation - Oestrogen
- Oestrogen is metabolised by CYP 3A4 (phase 1 reaction)
- Oestrogen is also conjugated in the liver (phase 2 reaction) and excreted in the bile
- Bacteria in the intestine hydrolyse the conjugate and release free oestrogen
- This free oestrogen is then reabsorbed (enterohepatic circulation)
What is the Volume of Distribution of a drug?
How is it calculated?
Volume of Distribution (VD) of a drug = a measure of the extent to which the drug leaves the blood and distributes into the tissues
- It is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood/plasma
- It is calculated by the following formula
What is the volume of distribution of a drug that:
- Remains primarily in the blood?
- Distributes primarily into the extracellular fluid?
- Distributes freely throughout the tissues?
Volume of Distribution (VD)
- Some drugs tend to remain primarily in the blood e.g. those which are highly protein bound and these drugs have a LOW volume of distribution
- Some drugs distribute primarily into the extracellular fluid and these drugs have an INTERMEDIATE volume of distribution
- Some drugs distribute freely throughout the tissues, or may be stored in the tissues e.g. fat stores, and these drugs have a HIGH volume of distribution
What are 4 examples of drug VDs?
Volume of Distribution (VD) - Examples
- Naproxen 8L
- Paracetamol 80L
- Digoxin 500L
- Chloroquine >7000L
What is the clinical significance of a drugs VD?
Volume of Distribution (VD) - Clinical Significance
- The volume of distribution gives information on the distribution of the drug in the body
- The volume of distribution helps in determining the correct dose, any loading dose, and whether the drug is dialysable (in treatment of overdose)
- The volume of distribution also affects the half-life of the drug, and the clearance of a drug
What is a Drugs half life?
Half Life (t1/2) of a drug = the time taken for the blood level of the drug to halve
What is First Order Kinetics in pharmacological terms?
Half Life (t1/2) and First Order Kinetics
- For most drugs the time taken to go from a blood level of 100μg/ml to 50μg/ml is the same time to go from 50μg/ml to 25μg/ml, and the same time to go from 25μg/ml to 12.5μg/ml etc
- The blood level halves every half-life (t1/2), but the actual amount of drug eliminated each half-life varies
- The rate of elimination is proportional to the drug concentration
- This is called first order kinetics, and this applies to the vast majority of drugs
What are some examples of the half lives of drugs?
What does half life determine clinically?
Half Life (t1/2)
- The half-lives of drugs can vary considerably
- Some examples are
- paracetamol = 3 to 4 hours
- ibuprofen = 2 hours
- methadone = 15 to 60 hours
- atorvastatin = 14 hours
- sertraline = 26 hours
- amiodarone = 14 to 110 days
- alendronate = 10 to 12 years
- The half-life is an important factor in determining the dosage interval (how often a drug is taken)
What is Steady State?
How long does it usually take to reach steady state?
Steady State
- With first order kinetics if a patient takes a drug regularly there comes a time when the amount of drug taken by the patient in each dose is equal to the amount of drug eliminated
- When this situation is reached it is referred to as “steady state“
- It takes around 5 half lives of a drug to reach steady state
What is Zero Order Kinetics in pharmacological terms?
Zero Order Kinetics
- A few compounds are excreted (eliminated, cleared) from the body by zero order kinetics
- With zero order kinetics a constant amount of drug is eliminated per unit of time
- With zero order kinetics the rate of elimination (clearance) is constant and independent of the amount of drug present in the body at the time
- With first order kinetics the rate of elimination (clearance) varies and is proportional to the amount of drug present at the time
How is Alcohol metabolised in the body?
Which kinetics is it excreted by?
How much alcohol can the average person metabolise per hour?
Metabolism of Alcohol
- Alcohol (ethyl alcohol) is excreted by zero order kinetics
- Alcohol (ethyl alcohol) is metabolised to acetaldehyde by the enzyme alcohol dehydrogenase
- Alcohol dehydrogenase becomes saturated at relatively low blood alcohol concentrations
- The average person can metabolise around 8 to 10 grams of alcohol per hour
- A standard drink contains 10 grams of alcohol
- The average person can thus metabolise (clear, eliminate) one standard drink per hour
What controls the rate of metabolism of alcohol?
What does this mean if someone consumes 2/4 standard drinks?
Metabolism of Alcohol
- The enzyme alcohol dehydrogenase becomes saturated
- This means that
- if someone consumes 2 standard drinks after an hour they will have one standard drink (10 grams of alcohol) left in the body
- if someone consumes 4 standard drinks after an hour they will have 3 standard drinks (30 grams of alcohol) left in the body
What blood alcohol level (BAC) does 1 standard drink give?
How much does the BAC reduce by per hour?
Alcohol Metabolism
- One standard drink (10 grams of alcohol) gives a blood alcohol level of approximately 0.015 grams per 100ml (0.015)
- The body can metabolise around 8 to 10 grams of alcohol per hour, and thus reduce the blood level by 0.015 per hour
- If a person has a blood alcohol level of 0.15 and they stop drinking, it will take approximately 10 hours to get to zero
What are Adverse Drug Reactions (ADRs)?
Adverse Drug Reactions (ADRs)
- All drugs produce adverse drug reactions (side effects, toxicity) - even a placebo will produce adverse reactions in some people
- ADRs are listed in the product information for each medicine
- Doctors, nurses, pharmacist etc. have a responsibility for counselling patients, and monitoring and documenting ADRs
- The Database of Adverse Event Notifications (DAEN) also provides information about ADRs
What are some examples of minor and severe/life threatening ADRs?
Adverse Drug Reactions (ADRs)
- Some adverse drug reactions are relatively minor - eg. dyspepsia, headache, nausea,
- Others maybe very severe and life threatening - eg. anaphylactic reaction e.g. amoxycillin
What are Type A (“augmented”) adverse reactions?
Give 3 examples?
How can these be resolved?
Type A ADRs
- Some adverse drug reactions are an extension of a drug’s therapeutic effect
- These are predictable and are often referred to as Type A (“augmented”) adverse reactions
- Examples:
- insulin may produce hypoglycaemia
- anticoagulants may produce bruising and bleeding
- antihypertensive therapy may produce dizziness and lightheadedness
- Can be treated by reducing the dose
What are Type B ADRs?
Give 1 example
Type B ADRs
- Some adverse drug reactions are unrelated to the therapeutic effect of the drug
- These reactions are unpredictable, rare, idiosyncratic, independent of the dose and may be severe
- They are often referred to as Type B (“bizarre”) adverse reactions
- Examples:
- anaphylactic reaction to penicillin
- Drug must be stopped and appropriate treatment initiated
What is Therapeutic Index of a drug?
What does a low/high TI mean?
Give examples of each?
Therapeutic Index of a drug = the ratio of the dose which produces adverse reactions (toxic, lethal) to the dose which produces the therapeutic response (LD50/ED50)
- Gives an indication of the safety margin of the drug
- Drugs with a low (narrow) therapeutic index have a low margin of safety
- e.g. digoxin
- Drugs with a high (wide) therapeutic index have a high margin of safety
- e.g. benzodiazepines
